Biomedical subjects
Publications and source records attributed to A Chesley.
This review will present a summary of a description of apoptotic pathways in the heart, followed by ways to measure it and the experimental and clinical evidence for the role of apoptosis in cardiac disease. An evaluation of the effectiveness of pharmacological and other therapeutic interventions in the prevention of apoptosis in the context of cardiac disease will also be presented.
Recent studies have shown that chronic beta-adrenergic receptor (beta-AR) stimulation alters cardiac myocyte survival in a receptor subtype-specific manner. We examined the effect of selective beta(1)- and beta(2)-AR subtype stimulation on apoptosis induced by hypoxia or H(2)O(2) in rat neonatal cardiac myocytes. Although neither beta(1)- nor beta(2)-AR stimulation had any significant effect on the basal level of apoptosis, selective beta(2)-AR stimulation protected myocytes from apoptosis. beta(2)-AR stimulation markedly increased mitogen-activated protein kinase/extracellular signal-regulated protein kinase (MAPK/ERK) activation as well as phosphatidylinositol-3'-kinase (PI-3K) activity and Akt/protein kinase B phosphorylation. beta(1)-AR stimulation also markedly increased MAPK/ERK activation but only minimally activated PI-3K and Akt. Pretreatment with pertussis toxin blocked beta(2)-AR-mediated protection from apoptosis as well as the beta(2)-AR-stimulated changes in MAPK/ERK, PI-3K, and Akt/protein kinase B. The selective PI-3K inhibitor, LY 294002, also blocked beta(2)-AR-mediated protection, whereas inhibition of MAPK/ERK activation at an inhibitor concentration that blocked agonist-induced activation but not the basal level of activation had no effect on beta(2)-AR-mediated protection. These findings demonstrate that beta(2)-ARs activate a PI-3K-dependent, pertussis toxin-sensitive signaling pathway in cardiac myocytes that is required for protection from apoptosis-inducing stimuli often associated with ischemic stress.
The time course for the activation of glycogen phosphorylase (Phos) and pyruvate dehydrogenase (PDH) and their allosteric regulators was determined in human skeletal muscle during repeated bouts of maximal exercise. Six subjects completed three 30-s bouts of maximal isokinetic cycling separated by 4-min recovery periods. Muscle biopsies were taken at rest and at 6, 15, and 30 s of exercise during bouts 1 and 3. Phos was rapidly activated within the first 6 s of bout 1 from 12% at rest to 47% at 6 s. The activation of PDH increased from 14% at rest to 48% at 6 s and 95% at 15 s of bout 1. Phos reverted back to basal values at the end of the first bout, whereas PDH remained fully activated. In contrast, in the third bout, PDH was 42% at rest and was activated more rapidly and was nearly completely activated by 6 s, whereas Phos remained at basal levels (range 14-20%). Lactate accumulation was marked in the first bout and increased progressively from 2.7 to 76.1 mmol/kg dry wt with no further increase in bout 3. Glycogen utilization was also marked in the first bout and was negligible in bout 3. The rapid activation of Phos and slower activation of PDH in bout 1 was probably due to Ca(2+) release from the sarcoplasmic reticulum. Lactate accumulation appeared to be due to an imbalance of the relative activities of Phos and PDH. The increase in H(+) concentration may have served to reduce pyruvate production by inhibiting Phos transformation and may have simultaneously activated PDH in the third bout such that there was a better matching between pyruvate production and oxidation and minimal lactate accumulation. As each bout progressed and with successive bouts, there was a decreasing ability to stimulate substrate phosphorylation through phosphocreatine hydrolysis and glycolysis and a shift toward greater reliance on oxidative phosphorylation.
We previously demonstrated that subsarcolemmal (SS) and intermyofibrillar (IMF) mitochondrial subfractions import proteins at different rates. This study was undertaken to investigate 1) whether protein import is altered by chronic contractile activity, which induces mitochondrial biogenesis, and 2) whether these two subfractions adapt similarly. Using electrical stimulation (10 Hz, 3 h/day for 7 and 14 days) to induce contractile activity, we observed that malate dehydrogenase import into the matrix of the SS and IMF mitochondia isolated from stimulated muscle was significantly increased by 1.4-to 1.7-fold, although the pattern of increase differed for each subfraction. This acceleration of import may be mitochondrial compartment specific, since the import of Bcl-2 into the outer membrane was not affected. Contractile activity also modified the mitochondrial content of proteins comprising the import machinery, as evident from increases in the levels of the intramitochondrial chaperone mtHSP70 as well as the outer membrane import receptor Tom20 in SS and IMF mitochondria. Addition of cytosol isolated from stimulated or control muscles to the import reaction resulted in similar twofold increases in the ability of mitochondria to import malate dehydrogenase, despite elevations in the concentration of mitochondrial import-stimulating factor within the cytosol of chronically stimulated muscle. These results suggest that chronic contractile activity modifies the extra- and intramitochondrial environments in a fashion that favors the acceleration of precursor protein import into the matrix of the organelle. This increase in protein import is likely an important adaptation in the overall process of mitochondrial biogenesis.
The mitochondrial phenotype within cardiac muscle cells is dramatically altered by thyroid hormone. We report here that this can be accounted for, in part, by modifications in the rate of mitochondrial protein import. The import of matrix-localized precursor proteins malate dehydrogenase (MDH) and ornithine carbamoyltransferase was augmented, whereas the insertion of the outer membrane protein Bcl-2 was unaffected by thyroid hormone treatment. Coincident with increases in the import of these matrix-localized precursors were thyroid hormone-induced elevations in the outer membrane receptor Tom20 and the matrix heat-shock protein mthsp70. The phospholipid cardiolipin was not involved in mediating the thyroid hormone-induced increase in import, as judged from adriamycin inhibition studies. When the import reaction was supplemented with rat heart cytosol, we found that 1) MDH import was stimulated, but Bcl-2 import was inhibited and 2) thyroid hormone did not influence the effect of the cytosol on import rates. Thus distinct requirements exist for the mitochondrial import of precursor proteins, destined for different organellar compartments. Although import of these matrix-localized proteins was augmented by thyroid hormone treatment, the proteolysis of matrix proteins was unaffected as indicated by the degradation of cytob2(167)RIC-dihydrofolate reductase, a chimeric protein missorted to the matrix. Thus our data indicate that at least some thyroid hormone-induced modifications of the mitochondrial phenotype occur due to the compartment-specific upregulation of precursor protein import rates, likely mediated via changes in the expression of protein import machinery components.
This study examined the effects of caffeine (Caf) ingestion on muscle glycogen use and the regulation of muscle glycogen phosphorylase (Phos) activity during intense aerobic exercise. In two separate trials, 12 untrained males ingested either placebo (Pl) or Caf (9 mg/kg body wt) 1 h before cycling at 80% maximum O2 consumption (VO2 max) for 15 min. Muscle biopsies were obtained from the vastus lateralis at 0, 3, and 15 min of exercise. In this study, glycogen "sparing" was defined as a 10% or greater reduction in muscle glycogen use during exercise after Caf ingestion compared with Pl. Muscle glycogen use decreased by 28% (Pl 255 +/- 38 vs. Caf 184 +/- 24 mmol/kg dry muscle) after Caf in six subjects [glycogen sparers (Sp)] but was unaffected by Caf in six other subjects [nonsparers (NSp), Pl 210 +/- 35 vs. Caf 214 +/- 37 mmol/kg dry muscle]. In both groups, Caf significantly increased resting free fatty acid concentration, significantly increased epinephrine concentration by twofold during exercise, and increased the Phos a mole fraction at 3 min of exercise compared with Pl, although not significantly. Caf improved the energy status of the muscle during exercise in the Sp group: muscle phosphocreatine (PCr) degradation was significantly reduced (Pl 47.9 +/- 3.6 vs. Caf 40.4 +/- 6.7 mmol/kg dry muscle at 3 min) and the accumulations of free ADP and free AMP (Pl 6.8 +/- 1.3 vs. Caf 3.1 +/- 1.4 micromol/kg dry muscle at 3 min; Pl 8.7 +/- 0.8 vs. Caf 4.7 +/- 1.1 micromol/kg dry muscle at 15 min) were significantly reduced. Caf had no effect on these measurements in the NSp group. It is concluded that the Caf-induced decrease in flux through Phos (glycogen-sparing effect) is mediated via an improved energy status of the muscle in the early stages of intense aerobic exercise. This may be related to an increased availability of fat and/or ability of mitochondria to oxidize fat during exercise preceded by Caf ingestion. It is presently unknown why the glycogen-sparing effect of Caf does not occur in all untrained individuals during intense aerobic exercise.
BACKGROUND: The American Cancer Society National Prostate Cancer Detection Project (ACS-NPCDP) was established in 1987. The experience of the ACS-NPCDP demonstrates the yield and impact of periodic examinations for the early detection of prostate cancer. METHODS: A cohort of 2999 well men ages 55-70 years was tested annually at 10 clinical centers by prostate specific antigen (PSA), transrectal ultrasound (TRUS), and digital rectal examination (DRE). Biopsies were performed on men with suspicious findings. Pathologic findings were reviewed. The initial study outcomes were the detection yield of multimodality testing and the comparative sensitivity and specificity of the different tests employed. Longer term outcomes included patient quality of life and survival. RESULTS: The cancer detection rate declined significantly across the years of intervention. DRE had lower sensitivity than TRUS or PSA, particularly in later years of follow-up. The specificity of TRUS was lower than that of DRE. Fewer than 9% of the cancers detected in this study were clinically advanced at the time of diagnosis. Ninety-four percent of patients in whom cancer was detected are alive after an average follow-up of 54 months. In one case, death occurred after surgery. Two deaths were attributed to prostate cancer, and eleven other deaths were unrelated to prostate cancer or its treatment. CONCLUSIONS: Results of the ACS-NPCDP indicate that a combined-modality approach to prostate cancer detection yields high levels of early detection with infrequent adverse outcomes. Continued follow-up is required to evaluate long term morbidity and mortality.
BACKGROUND: The American Cancer Society-National Prostate Cancer Detection Project (ACS-NPCDP) is a multidisciplinary evaluation of early prostate cancer detection interventions. This report summarizes the experience of the investigators to date and describes the overall and relative performance of the different detection modalities studied in this project. METHODS: Two thousand nine hundred ninety-nine men aged 55 to 70 years at entry who were not already under evaluation for prostate cancer were recruited to participate in up to 5 annual examinations by prostate specific antigen (PSA), digital rectal examination (DRE), and transrectal ultrasound (TRUS). In the course of 5 years of intervention, ACS-NPCDP investigators have completed 9937 examinations, recommended 1215 biopsies, and detected 203 cancers. RESULTS: Loss to cohort follow-up was greatest in the first year. Overall, TRUS led to twice the number of recommendations for biopsy compared with DRE (8.9% versus 4.4%). Elevated PSA was observed in 13.0% of 9535 measurements performed. The overall cancer detection rate declined significantly during the five years of intervention. Detection was significantly associated with age and symptom status at entry. DRE had lower sensitivity compared with TRUS or PSA, particularly in later years of follow-up. The specificity of TRUS was lower than that for DRE. PSA was elevated in 69.2% of examinations that led to cancer detection, compared with only 10.9% when cancer was not found. PSA level, PSA density, and PSA change were all related to the presence of cancer. Less than 6% of the cancers detected in this study were clinically advanced at the time of diagnosis. CONCLUSIONS: These data quantify the yield of early cancer detection that may be expected when PSA, DRE, and TRUS are used in populations comparable to the men participating in the ACS-NPCDP. Continued follow-up and further research is needed to assess whether men receiving early prostate cancer interventions benefit as a result.
This study examined muscle glycogenolysis and the regulation of glycogen phosphorylase (Phos) activity during 15 min of cycling at 85% of maximal O2 consumption (VO2max) in control and high free fatty acid (FFA; Intralipid-heparin) conditions in 11 subjects. Muscle biopsies were sampled at rest and 1, 5, and 15 min of exercise, and glycogen Phos transformation state (%Phos alpha), substrate (Pi, glycogen), and allosteric regulator (ADP, AMP, IMP) contents were measured. Infusion of intralipid elevated plasma FFA from 0.32 +/- 0.04 mM at rest to 1.00 +/- 0.04 mM just before exercise and 1.12 +/- 0.10 mM at 14 min of exercise. In the control trial, plasma FFA were 0.36 +/- 0.04 mM at rest and unchanged at the end of exercise (0.34 +/- 0.03 mM). Seven subjects used less muscle glycogen (46.7 +/- 7.6%, mean +/- SE) during the Intralipid trial, and four did not respond. In subjects who spared glycogen, glycogen Phos transformation into the active (alpha) form was unaffected by high FFA except for a nonsignificant reduction during the initial 5 min of exercise. Total AMP and IMP contents were not significantly different during exercise between trials, but total ADP was significantly lower with Intralipid only at 15 min. The calculated free ADP, AMP, and Pi contents were lower with Intralipid but not significantly different. However, when the present results were pooled with the data from a previous study using the same protocol [Dyck et al., Am. J. Physiol. 265 (Endocrinol, Metab. 28): E852-E859, 1993], the free ADP, AMP, and Pi contents of all subjects who spared glycogen (n = 13) were significantly lower at 15 min in the Intralipid trial. The findings suggest that the elevation of plasma FFA during intense cycling spares muscle glycogen by posttransformational regulation of Phos. This may be due to blunted increases in the contents of AMP, an allosteric activator of Phos alpha, and Pi, a substrate for Phos.
The purpose of this study was to examine the regulation (hormonal, substrate, and allosteric) of muscle glycogen phosphorylase (Phos) activity and glycogenolysis after short-term endurance training. Eight untrained males completed 6 days of cycle exercise (2 h/day) at 65% of maximal O2 uptake (Vo2max). Before and after training subjects cycled for 15 min at 80% of Vo2max, and muscle biopsies and blood samples were obtained at 0 and 30 s, 7.5 and 15 min, and 0, 5, 10, and 15 min of exercise. Vo2max was unchanged with training but citrate synthase (CS) activity increased by 20%. Muscle glycogenolysis was reduced by 42% during the 15-min exercise challenge following training (198.8 +/- 36.9 vs. 115.4 +/- 25.1 mmol/kg dry muscle), and plasma epinephrine was blunted at 15 min of exercise. The Phos a mole fraction was unaffected by training. Muscle phosphocreatine utilization and free Pi and AMP accumulations were reduced with training at 7.5 and 15 min of exercise. It is concluded that posttransformational control of Phos, exerted by reductions in substrate (free Pi) and allosteric modulator (free AMP) contents, is responsible for a blunted muscle glycogenolysis after 6 days of endurance training. The increase in CS activity suggests that the reduction of muscle glycogenolysis was due in part to an enhanced mitochondrial potential.
The purpose of this study was to determine whether an epinephrine (Epi) infusion would enhance muscle glycogenolysis during intense aerobic exercise. Epi was infused at rates that produced the same plasma Epi concentrations observed after caffeine (Caf) ingestion. Seven male subjects cycled for 15 min at 80% maximal O2 uptake during four different trials. Trial 1 was preceded by a 9 mg/kg oral dose of Caf to determine resting and exercise plasma Epi concentrations. Trial 2 was used to determine the Epi infusion rates needed to mimic the plasma Epi levels found with Caf. Trials 3 and 4 were randomized and consisted of either an Epi infusion or a saline infusion (control, Con). During Epi and Con trials muscle samples were obtained from the vastus lateralis at 0, 3, and 15 min of exercise. Plasma Epi levels were similar between Caf and Epi and were elevated twofold compared with Con. At 5 min of exercise the plasma Epi concentrations were 1.51 +/- 0.26, 2.61 +/- 0.34, and 2.97 +/- 0.45 nM for the Con, Caf, and Epi trials, respectively. Plasma Epi increased to 3.08 +/- 0.56, 5.45 +/- 1.11, and 5.86 +/- 1.03 nM at 14 min of exercise in the Con, Caf, and Epi trials, respectively. Muscle glycogenolysis was not different between trials (Con 220.5 +/- 25.3 vs. Epi 240.6 +/- 12.1 mmol/kg dry muscle). In addition, the degradation of muscle ATP and phosphocreatine and the accumulation of muscle lactate, ADP, and AMP were similar between trials.(ABSTRACT TRUNCATED AT 250 WORDS)
BACKGROUND: Different indexes that may enhance the early detection capability of prostate specific antigen (PSA) have been proposed. In addition to the indexes relating to the normal PSA level, there are data suggesting the usefulness of the PSA level relative to prostate gland volume (PSA density), age-referenced PSA level, and PSA change. Little research comparing the sensitivity and specificity of these measures in the same population has been reported. METHODS: All subjects were participants in the American Cancer Society National Prostate Cancer Detection Project. Specificity was studied in 2011 men without prostate cancer, and sensitivity was determined for 171 men with prostate cancer. RESULTS: Prostate specific antigen change showed the highest specificity (96.4%), and PSA density the lowest (85.3%). The most sensitive index was PSA density, which was positive for 74.7% of the 171 cases of known cancer. A PSA change of more than 0.75 ng/ml per year was the least sensitive index (54.8%). Sensitivity and specificity varied in a narrow range. Improved performance in specificity was achieved only with the loss of sensitivity. CONCLUSIONS: None of the alternative indexes commonly used in general early detection practice demonstrated particular advantage when compared with the normal PSA concentration, defined as no more than 4.0 ng/ml.
The American Cancer Society-National Prostate Cancer Detection Project is a prospective, comparative study of a cohort of 2,999 men 55 to 70 years old not suspected on entry of having prostate cancer. A total of 164 prostate cancers is available from this project for analysis. A small proportion of tumors detected were advanced in terms of the clinical stage at diagnosis. Cancer detected by digital rectal examination tended to be more advanced than that found on the basis of only transrectal ultrasound or prostate specific antigen (PSA). A large proportion of patients received curative therapy involving radical prostatectomy in 67.1% and radiotherapy in 18.3%. Of 103 men presumed to have organ confined disease and treated by prostatectomy 64 (37.9%) actually had locally extensive cancer pathologically. PSA level and PSA density were associated with the detection of organ confined cancer but several advanced tumors had PSA levels in the normal range. Age referenced PSA, compared to conventional standards, demonstrated lower sensitivity to cancer with little improvement in specificity. The disease resulting from this multimodality detection effort represented a spectrum of pathological conditions. Further followup and evaluation are needed to determine whether these benefits are reflected in long-term mortality and survival experience.
This study examined whether high physiological concentrations of epinephrine (EPI) would enhance muscle glycogenolysis during intense muscular contractions. Muscles of the rat hindlimb were perfused for 12 min at rest and 45 s of tetanic stimulation (1.0-Hz train rate, 100-ms train duration at 80 Hz) without EPI (control) or with 15 or 35 nM EPI. In the EPI groups the muscles were perfused with EPI for the last 2 min of rest perfusion and throughout stimulation. Glycogenolysis in the white gastrocnemius, red gastrocnemius, plantaris, and soleus muscles during stimulation was unaffected by the presence of EPI in the perfusion medium. In addition, muscle lactate and hindlimb lactate efflux were similar in EPI and control groups. It is concluded that EPI is not important for enhancing glycogenolysis in rat muscles composed predominantly of fast-twitch fibers during intense short-term tetanic stimulation.
BACKGROUND: Few data are available to describe the clinical and pathologic characteristics of prostate cancers detected through early detection programs. The American Cancer Society National Prostate Cancer Detection Project (ACS-NPCDP) is a multimodality, multicenter study of the feasibility of early prostate cancer detection using digital rectal examination (DRE), transrectal ultrasound (TRUS), and prostate specific antigen (PSA). One hundred fifty-six prostate cancers are available from this project for analysis. METHODS: The ACS-NPCDP is a prospective, comparative study of a cohort of 2,999 men between 55 and 70 years of age not suspected of having prostate cancer. DRE, TRUS, and PSA are performed for each subject on an annual basis for as long as 5 years. Biopsies are performed on the basis of recommendations from DRE or TRUS results. Although elevated PSA alone was not typically a basis for biopsy, in some instances biopsies were recommended because of the degree of elevation in PSA. Diagnoses are confirmed by participating pathologists and by pathologic analysis. RESULTS: A small proportion of cancers detected were advanced in terms of the clinical stage at time of diagnosis. A total of only six cancers were stage C1 to D1, and five of these were preexisting cancers detected at the first examination. Cancers detected by DRE tended to be more advanced than those found on the basis of only TRUS or PSA. A large proportion of patients received curative therapy, involving radical prostatectomy for 67.9% and radiation therapy for 17.9%. Of 100 men presumed to have organ confined disease and treated by prostatectomy, 64 actually proved to have localized cancer, a rate of upstaging of 36.0%. PSA level and PSA density were associated with the detection of organ confined cancer, but several advanced cancers had PSA levels in the normal range, limiting the usefulness of these measures for staging. CONCLUSIONS: The cancers resulting from this multimodality detection effort represented a spectrum of pathologic findings. These data, however, suggest that early detection interventions in men not suspected to have prostate cancer will yield tumors with a favorable stage distribution that are likely to benefit from treatment. Further follow-up evaluation is needed to determine whether these benefits are reflected in long-term mortality and survival experience.
BACKGROUND: The American Cancer Society-National Prostate Cancer Detection Project is a prospective study of the feasibility of early prostate cancer detection by digital rectal examination (DRE), transrectal ultrasound (TRUS), and prostate specific antigen (PSA). Two thousand nine hundred ninety-nine men not previously suspected of having prostate cancer have been entered on study in ten participating clinical centers. METHODS: The study protocol requires these men to undergo testing with the three detection methods under investigation on an annual basis for up to 5 years. Data currently are available on 1972 men who have completed protocol requirements for two sequential series of examinations. RESULTS: At the first visit, it was recommended that 16.5% of subjects undergo biopsy based on the TRUS and/or DRE findings. Seventy-three (3.7%) men were found to have cancer after the first series of examinations. When the 1899 men who did not have cancer were reexamined, in 11.4%, a biopsy was recommended, and an additional 33 (1.7%) cancers were detected. Cancer detection rates were higher in older men, and the sensitivity of TRUS was higher than that of DRE at both examinations. The positive predictive values (PPV) of TRUS and DRE varied significantly depending on the PSA level; PPV decreased at the second examination. Positive findings during the second examination were associated with elevated PSA levels during the earlier visit and rising PSA levels between examinations. Analyses of the 106 cancers detected currently showed a preponderance of early-stage cancer and low Gleason scores. CONCLUSIONS: It may be possible to increase the early detection of prostate cancer by periodic examination by a combination of detection modalities.
The participating institutions of the American Cancer Society National Prostate Cancer Detection Project did 520 biopsies on 2425 men over a 3.5-year period. A total of 88 cancers were confirmed pathologically, 93% of which clinically were organ confined. In 324 men (62.3%), a recommendation for biopsy was made based solely on the results of transrectal ultrasonography (TRUS); in 69 patients (13.3%), solely on the digital rectal examination (DRE); in 116 patients (22.3%), on abnormal DRE and TRUS examinations; and in 11 patients (2.1%), in whom DRE and TRUS were normal, on elevated prostate-specific antigen (PSA) levels. The TRUS was abnormal in 80.6% of men found to have cancer, and the PSA level and DRE were abnormal for 67% and 50% of cancers, respectively. The influence of PSA level on cancer detection increased as the serum level increased above 4 ng/ml. The positive predictive values of both the DRE and TRUS were influenced significantly by the presence of an elevated PSA level (P = 0.044 and P less than 0.001, respectively). The results of this ongoing multicenter study support the following statements: (1) the prostate cancer detection rate is influenced by this diagnostic triad and (2) the detection rate of organ-confined disease can be improved substantially by early detection programs.
The American Cancer Society National Prostate Cancer Detection Project is a prospective, multidisciplinary, and multicenter trial to assess the potential for early detection of prostate cancer by transrectal ultrasonography (TRUS), digital rectal examination (DRE), and serum prostate-specific antigen assay (PSA). By November 1990, 2805 men between the ages of 55 and 70 years with no known signs or symptoms of prostate cancer were enrolled in the study, which is planned to run for 5 years. Annual TRUS, DRE, and PSA tests were done on these subjects, and biopsies were recommended for suspicious lesions when detected. To study the performance of PSA testing in presumed normal subjects, all men were eliminated who had (1) prostate cancer detected on their initial examinations and proven by biopsy or (2) cancer detected during the year or subsequent examinations. Additionally, all men with TRUS or DRE findings that were interpreted as suspicious for cancer but who are being followed and have not yet had biopsies done were removed from this series. This left a unique, extensively screened group of 1695 men who were free of prostate cancer, as far as could be determined. Analyses of the PSA levels in this large population in the appropriate age range for increasing risk of prostate cancer revealed several important findings. First, there was a direct relationship between serum PSA levels and estimated prostate volume for both the currently available monoclonal and polyclonal PSA assays. Individuals with benign prostatic hyperplasia and larger gland volume have a higher normal limit of PSA than men with normal gland volume. Second, analyses showed no relationship between age and PSA levels or between symptoms of prostatism and PSA levels independent of gland enlargement. It was concluded that volume-adjusted upper limits of normal PSA can be determined for different levels of specificity desired. This information may be applicable to the use of PSA in men not already suspected of having prostate cancer and may increase its effectiveness as a tool for early detection.